System degeneration of the central nervous system (CNS) is one of the groups of neurologic diseases of unknown etiology. In this grant application, studies on the mechanisms of (1) slowly progressive neuronal degeneration and (2) transneuronal degeneration, two main pathologic processes involved in system degeneration, are proposed using the optic nervous system of rats. The optic nervous system would provide an excellent model because of its close similarity to the brain in terms of histogenesis, function, and biology, as well as its relatively simple fiber connections. Our preliminary studies showed that when the retina was mechanically scratched causing detachment and allowed to degenerate slowly in the vitreous fluid of one eye, non-inflammatory degeneration of photoreceptor cells was observed in the contralateral eye. The bipolar and ganglion cells also decreased in number. This interesting phenomenon, which we prefer to call "sympathetic retinopathy" (as opposed to the well known disease, sympathetic ophthalmia in which inflammatory lesions are mainly uveal) has been observed in a high percentage of adult rats but is difficult to produce in young animals. This phenomenon, which most likely represents an autoimmune process and might be related to slowly progressive neuronal loss in human system degeneration of CNS, will be tested in normal rats, rats with light-induced photoreceptor degeneration (O'Steen and Anderson, 1972), and rats with glutamate-induced bipolar and ganglion cell degeneration (Hansson, 1970d) in various combinations to determine the possible existence of immunologic properties of each of these neuronal elements. Thymectomized animals will also be used to test if cell-mediated immunity is operative in sympathetic retinopathy. Additional studies will involve sequential observation of transneuronal degeneration in light-and glutamate-treated animals as well as in rats with hereditary retinal degeneration. Special attention will be given to ultrastructural aspects of synapses in retina, lateral geniculate body, and, possibly, the visual cortex.